Existing therapeutic agents for Acute Myeloid Leukemia (AML) are inadequate to due poor efficacy and severe side effects. This is especially a problem in adults where the 5 year survival is less than 20-50%. Differentaition therapy for AML holds significant promise in leading to more efficacious and less toxic therapies. AML is a disease characterized by the arrest of differentiation of immature myeloid cells. After leukemic cells undergo terminal differentiation, they lose their ability to proliferate. The potential of differentiation therapy has been demonstrated by the use of the differentiation agent, ATRA, for one relatively uncommon subset of AML, acute promyelocytic leukemia. With the use of ATRA 75-85% of acute promyelocytic leukemia patients can now be cured. We have recently identified a novel differentiation-inducing agent, CLT731, that exhibits potent in vitro leukemia differentiation-inducing activity and preliminary evidence of mouse in vivo activity. CLT731 is an analogue of ellipticine, an agent that has perviously been found to have anti-tumor activity but also exhibits high toxicity. As CLT731 has preferential activity on leukemic cells, it appears to have a significantly reduced toxicity profile. The aims of this phase I project are to 1) demonstrate the promise of a CLT731 in mouse AML model systems 2) demonstrate the activity of this compound on patient samples in vitro and 3) to assess its potential toxicities. Due to the enormous need for novel AML therapeutics, especially agents with reduced toxicity, this work has the potential to improve the quality of life for patients with AML. PUBLIC HEALTH RELEVANCE: This project is highly relevant to public health as its main objective is to develop a novel therapy for patients with Acute Myeloid Leukemia that is both efficacious and has low toxicity. As the current AML therapeutics have low efficacy and high toxicities, there is a significant need for new therapies for AML.